The overall objective of this UH2 application is to develop a potent, selective and orally active GABA-A ?5 Positive Allosteric Modulator (PAM) for the treatment of Alzheimer?s Disease (AD) in its earliest symptomatic stages. The target of the GABA-A ?5 Positive Allosteric Modulator (PAM) is the occurrence of aberrant neural overactivity in the hippocampal network of the medial temporal lobe where early cellular degeneration occurs in this neurodegenerative disease. This phase of Alzheimer?s is often referred to as Mild Cognitive Impairment due to Alzheimer?s Disease (MCI due to AD), as patients progress to the symptomatic criteria for a clinical diagnosis of dementia. There are currently no approved therapeutics for this indication making this an area of extremely high unmet need. There is strong support from preclinical AD models that control of hyperactivity is efficacious. AgeneBio?s GABA-A ?5 PAM program represents a novel approach to addressing the excess hippocampal activity in this patient population at high risk for further progression. Recent preclinical and clinical studies using the atypical antiepileptic levetiracetam have supported the concept that reduction of hippocampal overactivity is beneficial. That same treatment has shown efficacy in multiple preclinical AD models of both amyloid and tau pathology. The strong hippocampal localization of GABA-A ?5 receptors coupled with its role to control tonic inhibition make GABA-A ?5 PAMs well suited to reduce the excess hippocampal activity in early AD. Through ongoing medicinal chemistry efforts, AgeneBio?s GABA-A ?5 PAM program is at a Discovery stage of lead optimization. The screening tree is well defined, all assays are in place, and compounds have advanced through the screening tree. Potent and selective GABA-A ?5 PAMS with good in vitro ADME properties and in vivo receptor occupancy have been identified. Additionally, several compounds demonstrate efficacy in vivo in a radial arm maze task in age-associated memory impaired rats. Improvements in blood brain barrier penetration and oral bioavailability are required in order to declare a lead compound ready for Development.